The Spectrum of Parathyroid Gland Dysfunction Associated with The

European Journal of Endocrinology (2006) 155 47–52 ISSN 0804-4643

CLINICAL STUDY The spectrum of parathyroid gland dysfunction associated with the microdeletion 22q11 Sylvie Hie´ronimus1, Magali Bec-Roche1, Florence Pedeutour2, Jean Claude Lambert2, Kathy Wagner-Malher3, Jean Christophe Mas3, Jean Louis Sadoul1 and Patrick Fe´nichel1 Departments of 1Endocrinology and Reproductive Medecine, 2Medical Genetics and 3Pediatrics, Nice University Hospital , BP 3079, 06202 Nice cedex 3, France (Correspondence should be addressed to S Hie´ronimus; Email: [email protected])

Abstract Objective: Clinical features associated with microdeletion of chromosome 22q11 (del(22)(q11)) are highly variable. Increased awareness of this condition is needed among specialists such as endocrinologists to reduce diagnostic delay and improve clinical care. The purpose of this study was to describe the phenotype of patients with del(22)(q11), focusing on parathyroid gland dysfunction. Design and methods: Charts of 19 patients, including one kindred of three, known to have del(22)(q11) diagnosed by ﬂuorescence in situ hybridization (FISH) were reviewed from the register of the department of Medical Genetics. Major clinical features including hypoparathyroidism phenotype were collected. Results: Parathyroid dysfunction was present in 8 out of 16 patients (50%). Six patients were diagnosed with overt hypoparathyroidism. Hypocalcemia manifested as laryngeal stridor within the ﬁrst days of life (nZ3), seizures in infancy (nZ1) and adolescence (nZ2). The connection between hypoparathyroidism and diagnosis of del(22)(q11) was belated at the median age of 18 years. One patient had presented with transient neonatal hypoparathyroidism, and one patient had latent hypoparathyroidism. Within the kindred family, the phenotype variability including that of parathyroid dysfunction was as marked as between unrelated individuals. Standard karyotype failed to detect the deletion in 15 out of 19 cases. Conclusions: Abnormal parathyroid function in the del(22)(q11) ranges from severe neonatal hypocalcemia to latent hypoparathyroidism. Del(22)(q11) should be considered as a potential cause of hypocalcemia even in young adult. When suspected, the diagnosis requires investigation by FISH. Furthermore, long-term calcemia follow-up is needed in normocalcemic patients with del(22)(q11) because of the possible evolution to hypocalcemic hypoparathyroidism.

European Journal of Endocrinology 155 47–52

Introduction genes, whereas 8% of patients have a smaller deletion of 1.5 megabases which contain 24 genes (2). Hypocalce- Microdeletion of chromosome 22q11 (del(22)(q11)) mia is invariably due to hypoparathyroidism, as occurs with an incidence of 1 per 4000 live births (1), originally described by DiGeorge in 1965 (4) and which places this disorder among the most common documented by the aplasia or hypoplasia of the genetic syndromes. As a consequence of the microdele- parathyroid glands at surgery or autopsy (5). In a very tion, there is a congenital failure in the development of large European cohort of patients known to have the derivatives of various pharyngeal arches and del(22)(q11), hypocalcemia was noted in 60% of pouches (2). Clinical features associated with patients (6). Usually hypoparathyroidism manifests del(22)(q11) are highly variable (3) and include one during the neonatal period (7). However, late-onset or more of the following main anomalies: congenital appearance of symptomatic hypocalcemia has been cardiac defects, hypocalcemia, immunodeﬁciency from reported in adolescence and adulthood (8,9). Due to thymic hypoplasia, palate anomalies and velopharyn- varying presentation and severity, the diagnosis of geal dysfunction, cognitive impairment, and minor chromosome 22q11 deletion syndrome is still often facial dysmorphy. Despite heterogeneous clinical pre- delayed. Increased awareness and knowledge among sentations, the genotype is remarkably homogenous the many specialists such as endocrinologists, who may with deletions present in the 22q11 region. Approxi- encounter these patients, is needed to reduce the mately 90% of patients have a typical deleted region diagnostic delay and provide optimal clinical care. The (TDR) of 3 megabases, which includes an estimated 30 purpose of this study was to describe the phenotype of a

q 2006 Society of the European Journal of Endocrinology DOI: 10.1530/eje.1.02180 Online version via www.eje-online.org

Downloaded from Bioscientifica.com at 09/27/2021 05:10:01AM via free access 48 S Hie´ronimus and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2006) 155 series of patients with del(22)(q11), diagnosed at Nice parents and siblings of the index patient. Informed University Hospital and especially to investigate the consent was obtained from parents or patients spectrum of parathyroid gland dysfunction. accordingtoageandabilitytoassent.

Subjects and methods Results We have retrospectively studied the charts of 19 The mean age of patients (11 males, 8 females) was patients, including one family of three individuals, 17G12 years when data were collected. Age at the known to have del(22)(q11) diagnosed by a fluor- diagnosis ranged from 7 days to 48 years (median 18 escence in situ hybridization (FISH) test at Nice years). Nine patients were born before FISH became a University Hospital between 1994 and 2004. The routine diagnostic test. Eight patients (42%) had been cases were identified from a register held by the diagnosed in adolescence or young adulthood. Familial department of Medical Genetics and included patients occurrence of the deletion was confirmed in 2 out of 13 followed in the departments of Pediatrics and Endocrin- tested kindred. One case included three individuals in ology of our hospital. The age at the diagnosis was set as two generations; two brothers (20 and 18 years old) and the age when the FISH test was performed. Based on their mother (48 years old). In the other case, the literature findings of the major clinical features of the affected patient’s mother had a 22q11 deletion detected 22q11 deletion, the following data were gathered from by FISH but no clinical data were available for her; thus, the patient’s medical records: congenital cardiac defect, she was not included in the study. In four cases, the palate anomalies including cleft palate or velophar- del(22)(q11) was visible by using conventional yngeal insufficiency, dysmorphic features, thymic hypo- R-banding karyotyping and was confirmed by FISH plasia noticed by the surgeon during the heart analysis. In 15 cases, the R-banded karyotypes were operation or history of recurrent infections, learning apparently normal (Fig 1A) whereas FISH studies difficulties, behavioral abnormalities and hypopara- demonstrated a deletion in the ‘DiGeorge chromosomal thyroidism. Assessment of parathyroid dysfunction region’ (Fig 1B). Major clinical findings are reported in included detailed clinical history inquiring into Table 1. Parathyroid dysfunction was present in 8 out of symptoms of hypocalcemia and the following 16 patients (50%). Based on frank hypocalcemia with biological features: concentrations of total calcium inappropriately low PTH concentration, six patients (normal range 2.2–2.6 mmol/l), phosphate (normal were diagnosed with overt hypoparathyroidism. Age at range 0.8–1.45 mmol/l), ionized calcium (normal the diagnosis ranged from neonatal period to 14 years. range 1.17–1.30 mmol/l), intact parathyroid hor- Hypocalcemia manifested as laryngeal stridor within mone (PTH) assessed by IRMA (Nichols Institute, the first days of life (nZ3), seizures in infancy (nZ1) California) (normal range 10–65 ng/l). Data regard- and adolescence (nZ2). However, the connection ing parathyroid involvement were available for 16 between hypoparathyroidism and diagnosis of deletion patients. Biochemical evaluation had been performed 22q11 was belated at the median age of 18 years. These in six patients because of clinical symptoms and in six patients were treated with 1,25-dihydroxyvitamin D the ten others, merely because of the discovery of and calcium supplementation. During adolescence, del(22)(q11). Metaphase cells from peripheral blood compliance to medication became poor in four patients lymphocytes (PBL) were prepared for standard due to behavioral disorders. They experienced recurrent chromosome analysis according to conventional general seizures and required intravenous treatment procedures. At least 16 RHG-banded metaphase with calcium. One patient, the mother of two affected cells were analyzed for each patient. FISH was boys, was considered to have latent hypoparathyroid- performed on metaphase cells from PBL according to ism. One patient, the elder son of the affected family, had the manufacturer’s recommendations using the presented with transient neonatal hypoparathyroidism. DG/VCFS critical region probes D22S75 (Oncor, Symptoms of hypocalcemia and biochemical findings B-Biogene, Illkirch, France) or TUPLE 1 (Vysis, within the three affected kindred from this family are Abbott Molecular Diagnostics, Rungis, France) reported in Table 2, illustrating the variability of located at 22q11.2. Both probes were used together hypoparathyroidism phenotype. The mother had a with the control probe, arylsulfatase-A (ARSA), at normal total calcium (2.30 mmol/l) but a low PTH 22q13.3. For each patient, at least 20 metaphase level(17ng/l)comparedtolowionizedcalcium cells were scored for both the D22S75 or TUPLE1 concentration (1.10 mmol/l) and high phosphate and ARSA signals. Deletions 22q11 were asserted concentration (1.78 mmol/l). She did not manifest for the D22S75 or TUPLE1 signals, but not the any symptoms of hypocalcemia, but the brain CT scan ARSA signals, which were consistently missing on showed multiple calcifications located in the basal one of the chromosome 22. Familial screening was ganglia and cerebellum. The elder son had presented done in 13 of 17 kindred: karyotype and FISH with laryngospasm, associated with hypocalcemia in analysis were performed on PBL samples from the the neonatal period. Calcium supplementation was

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Figure 1 R-banded karyotype (A) and FISH analysis (B) on peripheral blood lymphocyte metaphase cell from patient. The microdeletion is detected by the FISH analysis only. (A) the karyotype is 46,XX. No anomaly is detected. The two chromosome 22s are apparently similar in size (arrows). (B) Both TUPLE1 (DiGeorge region in 22q11; red signal) and ARSA (control probe at 22q13.3; green signal) loci are present on the normal chromosome 22 (arrow) whereas only ARSA is present on the other chromosome 22 (arrowhead), indicating a 22q11 microdeletion. discontinued at 3 months of age without recurrence of hypoparathyroidism was initiated at that time. In the symptom. Now 20 years old, he remains asympto- addition, a congenital cardiovascular anomaly was matic and has normal calcium, phosphate and PTH conﬁrmed in 11 patients. The most common defects levels. The youngest son had generalized seizures at 14 were ventricular septal defect (nZ6) and tetralogy of years of age and was treated with an antiepileptic drug. Fallot (nZ4). Truncus arteriosus was observed in one The biochemical evaluation performed four years later case. All patients had dysmorphic features such as revealed a severe hypocalcemia as demonstrated by minor auricular anomalies (thick helices, small or total calcium (1.74 mmol/l) and ionized calcium round ears) and/or prominent tubular nose, small (0.97 mmol/l) compared with undetectable serum arch-shaped mouth, hooded eyelids and hypertelorism. concentration of intact PTH. Treatment of Adolescent and adult patients showed more

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Table 1 Parathyroid dysfunction and major clinical features of the 22q11deletion for all patients.

Feature Age at leading to Parathyroid Manifestations Cardiac Dysmorphic Palate Learning Behavior Sex diagnosis diagnosis dysfunction of hypocalcemia defect features anomalies difﬁculties abnormalities

M7d Hypopara- C Neonatal laryn- K C K C K thyroidism geal stridor M8m Developmental K None KC K C C delay M8m Cardiac defect K None CC C C K M 9m Cardiac C Neonatal laryn- C C C C K defect geal stridor M3y Developmental K None CC C C K delay M3.5y Cardiac defect NA NA CC K C K M6y Cardiac defect K None CC K C C M18y Hypopara- C Seizures in K C C C C thyroidism adolescence M20y Cardiac C* Transient neo- C C K C K defect natal laryngo spasm M20y Hypopara- C Neonatal laryn- K C K C C thyroidism geal stridor M20y Cardiac defect NA NA CC C C C F7d Cardiac defect NA NA CC K C K F7d Cardiac defect K None CC K K K F7d Cardiac defect K None CC K K K F2y Cardiac defect K None CC K C C F15y Hypopara- C Seizures in ado- K C C C C thyroidism lescence F18y Hypopara- C Seizures in K C K C C thyroidism infancy F33y Abnormal K None KC C C C behavior F48y Dysmorphic C§ Intracranial calci- K C C K K features ﬁcations

Patients with parathyroid dysfunction are in bold. M, male; F, female; Age at diagnosis was set as the age when the FISH test was performed; m, months; y, years; d, day(s); NA, findings non available; C, clinical feature present; K, clinical feature absent; * transient hypoparathyroidism in neonatal period; §latent hypoparathyroidism. pronounced facial anomalies than neonates and young have been attributed to this disorder (DiGeorge children. Palate anomalies were reported in eight syndrome, velo-cardiofacial syndrome, conotruncal patients including submucous cleft palate (nZ3), anomaly face syndrome), illustrating the clinical velopharyngeal insufficiency and hypernasal speech variability of the phenotype associated with (nZ5). Hypoplasia of the thymus was suspected in two del(22)(q11). cases because of the failure to detect the thymic tissue In our series, parathyroid dysfunction was present in during surgical correction. Six patients had a history of 50% of the patients. Accurate assessment of the recurrent pharyngo-tracheal infections. All but 3 of the prevalence of hypoparathyroidism in del(22)(q11) 19 patients were considered to have developmental depends not only on the selection criteria used but delay or learning difficulties. Behavioral abnormalities also on recognition. Because mild or transient hypo- were reported in nine cases. Two patients had evidence calcemia may frequently be missed (13), a systematic of a psychiatric illness. screening is required for its detection. This was not done in our study. McDonald-McGinn et al. reported hypocalcemia in 77 of 158 (49%) patients with a confirmed Discussion del(22)(q11) (14). In a large European cohort, 60% of patients were hypocalcemic (6). Monoallelic microdeletion of chromosome 22q11 is Hypoparathyroidism is most likely to present with considered as the most common human deletion symptoms of hypocalcemia, seizures, tremors or tetany syndrome. However, as shown in the population-based in the neonatal period. Active transport of calcium from study in Western Sweden (1), the number of individuals mother to fetus is abruptly interrupted with birth and diagnosed depends on the experience and awareness of calcium intake within the first few days of life is the syndrome among specialists who encounter these insufficient to maintain normal calcium levels in patients, and also on the severity of the phenotype. Prior neonates with a reduced parathyroid reserve. In some to the discovery of the deletion (10–12), many names children, most likely those with severe parathyroid

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Table 2 Symptoms of hypocalcemia and biochemical ﬁndings within the three affected kindred from the same family.

Total calcium Ionized calcium Phosphate Intact PTH (mmol/l) (mmol/l) (mmol/l) (ng/l) Symptoms of (normal range (normal range (normal range (normal range hypocalcemia 2.2–2.6) 1.17–1.30) 0.85–1.45) 10–65)

Mother 48 years Intracranial calciﬁcations 2.30 1.10 1.78 17 Elder son* 20 years Transient laryngospasm 2.30 1.17 1.30 31 in neonatal period Youngest son 18 years Seizures in adolescence 1.74 0.97 1.90 !8

*Index case. defect, hypocalcemia is usually persistent, neonatal in the regular follow-up of patients with hypoparathyroidism being the primary manifestation of del(22)(q11) (21). del(22)(q11). All infants with congenital hypoparathy- Congenital cardiac defect is usually the first present- roidism should be thoroughly evaluated for other ing symptom of del(22)(q11) in children, reported in physical features and screened for the del(22)(q11) by about 60% of cases (22). This major clinical feature FISH. Symptomatic hypocalcemia may also manifest commonly leads to the diagnosis. In return, a high later in life (8–9,15). Two of our patients developed proportion of affected children have no cardiac defect general seizures at 14 years of age and were treated with and a risk of diagnostic delay (23) as illustrated by the anticonvulsant therapy. The diagnosis of PTH-deficient late mean age at the diagnosis in our study (18 years). hypocalcemia was initially missed and considered later Cohen et al. (24) have reviewed the phenotype features on. Based on the history of learning disability and of 126 adults with the del(22)(q11) (age at diagnosis O dysmorphic facial features, chromosome 22q11 del- 18 years). They presented much lower rates of etion syndrome was suspected and confirmed by FISH. congenital heart defects, cleft palate and psychiatric So, the diagnosis of del(22)(q11) should be entertained disorders than those reported in children. On the other even in adolescents and adults with hypocalcemia (9). hand, cognitive impairment and facial anomalies may As observed in the literature (16, 17), we have also be the key findings that could help clinicians identify the noted one case of transient severe neonatal hypocalce- syndrome in adults (24). The most recurrent symptoms mia with spontaneous resolution during infancy. shown by our patients were indeed typical facies and learning disabilities. Some facial anomalies, such Recurrence of hypoparathyroidism may be precipitated as bulbous nasal tip, may become more apparent with during periods of increased metabolic demand such as age (25). cardiopulmonary bypass (18). Finally, our study emphasizes that standard karyo- The del(22)(q11) typically occurs de novo, although it type often fails to detect the deletion. When suspected, is inherited in about 10–20% of cases with a marked the diagnosis of del22q11 requires investigation by FISH excess of maternally inherited deletions(14). Even analysis. It is therefore very important to make the within one kindred family, the phenotypic variability clinical information concerning the patient available to including that of parathyroid gland dysfunction, may be the cytogenetics laboratory and to specifically request as marked as between unrelated individuals (8). As the 22q11 microdeletion to be searched by FISH. illustrated in this study by the three affected members Moreover, it is worthy to ask for complementary FISH from the same family, the spectrum of parathyroid gland detection when patients had been tested by convention- dysfunction associated with del(22)(q11) ranges from al karyotype only, particularly if this karyotype has been symptomatic hypocalcemic hypoparathyroidism to done before 1992 when FISH techniques were not normocalcemia with abnormally low basal PTH levels. routinely available. This latent hypoparathyroidism may change over time and become apparent and symptomatic with increasing age or during the period of hypocalcemic stress such as Conclusions infectious disease, pregnancy or surgery (8). The inability to increase PTH secretion appropriate for The spectrum of parathyroid gland dysfunction associ- hypocalcemic stimulus can be demonstrated with a ated with del(22)(q11) ranges from severe neonatal provocative test using disodium edetate infusion (8, 19). hypocalcemia to latent hypoparathyroidism. Del(22) It is suggested that families with 22q11 syndrome (q11) should be considered as a potential cause of should be informed of the symptoms that might occur hypocalcemia even in young adult. Conversely, long- with hypocalcemia (20). Moreover, screening of term follow-up should be given to patients with abnormal parathyroid function should be considered normocalcemia in the del(22)(q11) because of its

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